甲状旁腺素促成骨作用的研究进展

甲状旁腺素(Parathyroid hormone,PTH)能够调节骨骼的合成代谢和分解代谢过程,通过影响包括成骨细胞、破骨细胞、骨骼内衬细胞、骨细胞等众多种类的细胞系,并激活多种信号途径,从而达到促进骨形成的作用.这取决于低剂量及间断性的给药方式.大量动物试验和临床研究,显示甲状旁腺素可有效的治疗骨质疏松.近年来动物实验发现甲状旁腺素也可有效的促进骨折愈合.甲状旁腺素作为骨形成促进剂,将广泛应用于临床治疗.     

中药促进骨折愈合在细胞分子水平的研究进展

中药被广泛应用于治疗骨折和骨质疏松等骨科相关疾病,已有许多动物实验和临床试验证明中药,如淫羊藿、骨碎补等可刺激骨再生和抑制骨再吸收,最终促进骨折愈合。许多细胞实验证明这些中药成分可上调胞内成骨性转录因子和成骨相关基因产物表达,诱导前成骨细胞成骨分化和刺激成骨细胞增殖,促进骨结节形成和基质矿化。同时也可上调胞内破骨性转录因子和破骨相关基因产物表达,抑制前破骨细胞破骨分化和破骨细胞骨再吸收活性。此外这些中药成分还可影响胞内信号通路发挥以上相同的作用。由此发现前成骨细胞和前破骨细胞中的成骨性和破骨性转录因子、转录因子调节的基因表达和信号通路是中药促进骨折愈合的主要分子机制,也是目前中药促进骨折愈合的研究热点。     

表皮生长因子受体信号通路对骨折愈合的生物学作用

骨折愈合过程中,骨髓间充质干细胞、软骨细胞、成骨细胞及破骨细胞都有各自特定的作用,任何一类细胞的功能异常都会影响骨折愈合。目前一些研究显示,EGFR信号通路参与调节骨髓间充质干细胞、软骨细胞、成骨细胞及破骨细胞的增殖、分化及凋亡等多种生物学过程,在此,作者对EGFR信号通路对骨折愈合过程中相关骨组织细胞的影响做一综述。     

低氧及相关因子对破骨细胞形成与活性的调节作用

破骨细胞是具有多个核的骨吸收细胞,来源于单核-巨噬细胞谱系,在骨的正常发育和改建、骨折的愈合及病理性骨吸收中起重要作用.现有的研究表明,破骨细胞前体细胞和破骨细胞属氧感应细胞,其分化和功能发挥可受控于低氧环境及其诱导产生的调节因子.低氧发生于组织的血供减少或中断时,低氧及相关的细胞因子(VEGF、FGF-2、IGF-I、TNF-α、TGF-β等0可通过引起局部微环境的酸化、促进骨髓中破骨细胞前体细胞的生成、趋化破骨细胞前体细胞、刺激成骨细胞RANKL的表达、延长成熟破骨细胞的生存期、活化成熟的破骨细胞等多种机制来调节破骨细胞的形成和活性.     

骨折早期调节RANKL表达对骨折愈合影响的实验研究

目的通过对大鼠股骨骨折早期局部应用重组人骨保护素Fc融合蛋白(OPG-Fc),研究调节骨保护素(OPG)和核因子-κB受体活化因子配体(RANKL)的表达变化对骨折早期的影响,探讨其表达调节方式及作用机制。方法 48只雌性SD大鼠随机分成实验组和对照组,每组24只。建立大鼠股骨骨折模型,于术后第7天、第14天、第21天、第28天4个时间节段分批处死模型,标本切片后通过HE染色观察骨折愈合情况,免疫组织化学染色研究破骨细胞数量变化。结果 HE染色示单纯骨折组呈典型骨折愈合过程,而骨折局部注射OPG组骨痂形成及改造提前,骨折愈合加速。免疫组织化学染色显示在第7天、第14天、第21天、第28天各个时间节段单纯骨折组破骨细胞计数值均高于骨折应用OPG组,差异有统计学意义(P0.05)。结论骨折早期调节RANKL表达,当RANKL/OPG比值减小时,骨折局部破骨细胞减少,骨痂形成增多,骨折愈合加速。     

原发性骨质疏松症的骨骼免疫机制研究进展

原发性骨质疏松症是以骨质减少,骨的微观结构退化为特征的,致使骨的脆性增加以及易于发生骨折的骨骼疾病。其发病机制与多种因素相关,除了传统的内分泌机制之外,一种新的骨骼免疫机制已逐渐被深入研究:通过免疫细胞T淋巴细胞和B淋巴细胞、树突状细胞等,分泌多种细胞因子,并与多种细胞因子相互作用,通过信号通路的正负反馈调控,精细调节成骨细胞和破骨细胞的分化与增殖平衡,从而影响原发性骨质疏松症的发生。与破骨形成相关的T细胞,Th17细胞通过双重机制调控骨质吸收,Th1和Th2细胞亚群分别分泌IFN-γ和IL-4,通过抑制破骨细胞前体细胞发育成成熟的破骨细胞,从而抑制骨质吸收。Treg细胞通过表达CTLA-4,促进破骨细胞前体细胞的凋亡,抑制骨质吸收。B淋巴细胞通过调控RANKL和OPG的比例参与骨质代谢。树突状细胞既可以与CD4+T细胞结合,启动经典的RANKL/RANK破骨细胞形成的信号通路,参与骨质疏松的形成;也可以作为破骨细胞前体细胞的方式,在M-CSF等炎性因子的刺激下,直接分化为破骨细胞。现就这种免疫细胞与细胞因子精细调节骨质生成与骨质吸收平衡作用机制的最新研究进展进行阐述。     

神经组织损伤与骨折愈合及异位骨化

骨折愈合、异位骨化是一个极其复杂的生物学过程，涉及多种细胞、细胞因子的协同作用。本文综述了神经因素调节骨折愈合、异位骨化机制中神经组织及其所含神经肽、神经生长因子等对骨折愈合、异位骨化的影响。     

富含半胱氨酸蛋白61在骨形成与修复中的作用

与细胞外基质相关的富含半胱氨酸61(CYR61/CCN1)是CCN家族成员之一,可调节细胞的黏附、迁移、增殖和分化,并在胚胎形成和肿瘤发生与形成过程中发挥重要作用;也被认为是成血管因子,可促进血管形成.CYR61/CCN1在骨形成和骨折愈合过程中均有表达,抑制其在骨折中的作用可明显抑制骨折愈合.在研究CYR61/CCN1的成血管等作用基础上,进一步研究其在骨形成与骨修复中的作用及作用机制,有助于促进对骨形成与骨折愈合机制的新认识.对CYR61/CCN1在骨生物学中的作用及其机制研究,也可为骨形成和骨折愈合方面的研究带来新发现和新方向.     

创伤性脑损伤促进骨折愈合机制研究进展

目的 总结创伤性脑损伤（traumatic brain injury,TBI）促进骨折愈合相关机制的研究进展,为临床治疗骨折不愈合提供理论依据。方法 查阅国内外关于TBI促进骨折愈合的研究文献,从神经、体液及免疫3个方面总结TBI在骨折愈合中的作用,探讨骨折不愈合治疗新思路。结果 大量研究表明,骨折合并TBI患者的骨折愈合速度较单纯骨折患者更快。骨折合并TBI患者体液中各种细胞因子、激素的表达量明显高于单纯骨折患者;神经系统释放的神经因子透过受损血脑屏障到达骨折部位,同时合并TBI的骨折端炎症细胞和炎症因子的趋化、聚集与单纯骨折患者也有显著差异。复杂的体液、神经及免疫调节网络共同促进骨折端血管再生、成骨细胞分化并抑制破骨细胞活性。结论 TBI通过复杂的神经、体液及免疫调节网络促进骨折愈合,提示通过干预骨折周围微环境可以治疗骨折不愈合。     

NO及其调控物NOS在骨折愈合中的作用

一氧化氮(nitric oxide,NO)极易透过生物膜,是细胞间、细胞内的信使分子,其扩散速度快、穿透细胞膜的能力强、本身不稳定.由于其合成易于调节,作为高级生物体调节第二信使和神经递质,可有效地调节细胞与细胞间信息传递,在循环、呼吸、消化及内分泌代谢等系统中发挥着重要作用.目前的研究证实,NO与骨组织细胞功能关系密切.多种细胞因子、机械应激和激素等因素均可影响NO的生成.NO通过调节破骨细胞和成骨细胞的活性、调节骨代谢、影响骨组织血运、接受应力刺激、维持骨形态、参与骨折愈合.……     

针灸对实验性骨质疏松性骨折愈合影响的研究

目的 探讨针灸对骨质疏松性骨质愈合的作用。方法 采用12月龄雌性大鼠60只,摘除双侧卵巢法建立骨质疏松,模型3个月后作右股骨中段闭合骨折,随机分为对照组、模型组、雌二醇组、针刺组、艾灸组,分别于骨折后7、14、28天处死,并进行血清生化、骨痂BMP和组织学的观察。结果 骨折后第14天S－E2、S－BGP含量及BMP光密度值,针刺组和艾灸组较模型组之间的差别有显著性意义（P＜0.05）,至28天接近对照组;14天时软骨细胞及破骨细胞数量模型组较针刺组、艾灸组和雌二醇组稍多;28天时,各组骨痂均较成熟,但模型组呈疏松比表现。结论 针灸具有促进骨质疏松性骨质愈合的作用。     

针灸促进骨折愈合的红外热像图观察

目的通过红外热像图动态观察针灸对骨折愈合的作用.方法纯种新西兰家兔52只,随机分为对照组、针刺组和艾灸组,在手术直视下用咬骨钳在双侧桡骨中下1/3处造成3mm骨缺陷的标准骨折模型,造模后第二天起进行针灸治疗.针刺组取足三里、太溪、曲池、合谷4穴,艾灸组用大杼、肾俞、阿是穴,双侧交替,分别在造模前及造模后对骨折局部肢体进行红外线热像仪扫描,并用计算机图像处理系统计算骨折局部的温度值.结果术前各组皮温无明显差别,术后第4天均有降低,第11天时两个治疗组明显高于对照组(P＜0.05),而第18天时两个治疗组明显低于对照组.结论针灸疗法具有活血化瘀功能,能改善局部微循环而促进骨折愈合.     

Fracture healing in osteoporotic fractures: is it really different? A basic science perspective

Osteoporosis is a major health problem characterized by compromised bone strength that predisposes patients to an increased risk of fracture. Osteoporotic patients differ from normal subjects in bone mineral composition, bone mineral content, and crystallinity. Poor bone quality in patients with osteoporosis presents the surgeon with difficult treatment decisions. Much effort has been expended on improving therapies that are expected to preserve bone mass and thus decrease fracture risk. Manipulation of both the local fracture environment in terms of application of growth factors, scaffolds and mesenchymal cells, and systemic administration of agents promoting bone formation and bone strength has been considered as a treatment option from which promising results have recently been reported. Surprisingly, less importance has been given to investigating fracture healing in osteoporosis. Fracture healing is a complex process of bone regeneration, involving a well-orchestrated series of biological events that follow a definable temporal and spatial sequence that may be affected by both biological factors, such as age and osteoporosis, and mechanical factors such as stability of the osteosynthesis. Current studies mainly focus on preventing osteoporotic fractures. In recent years, the literature has provided evidence of altered fracture healing in osteoporotic bone, which may have important implications in evaluating the effects of new osteoporosis treatments on fracture healing. However, the mechanics of this influence of osteoporosis on fracture healing have not yet been clarified and clinical evidence is still lacking.     

Recombinant human platelet‐derived growth factor BB (rhPDGF‐BB) and beta‐tricalcium phosphate/collagen matrix enhance fracture healing in a diabetic rat model

Diabetes mellitus is a common systemic disease that has been associated with poor fracture healing outcomes. The mechanism through which diabetes impairs bone regeneration is unknown. One possible mechanism may be related to either decreased or uncoordinated release of local growth factors at the fracture site. Indeed, previous studies have found reduced platelet‐derived growth factor (PDGF) levels in the fracture callus of diabetic rats, suggesting that local application of PDGF may overcome the negative effects of diabetes and promote fracture healing. To test this hypothesis, low (22 µg) and high (75 ug) doses of recombinant human PDGF‐BB (rhPDGF‐BB) were applied directly to femur fracture sites in BB Wistar diabetic rats that were then compared to untreated or vehicle‐treated animals. rhPDGF‐BB treatment significantly increased early callus cell proliferation compared to that in control specimens. Low dose rhPDGF‐BB treatment significantly increased callus peak torque values (p < 0.05) at 8 weeks after fracture as compared to controls. High dose rhPDGF‐BB treatment increased callus bone area at 12 weeks postfracture. These data indicate that rhPDGF‐BB treatment ameliorates the effects of diabetes on fracture healing by promoting early cellular proliferation that ultimately leads to more bone formation. Local application of rhPDGF‐BB may be a new therapeutic approach to treat diabetes‐impaired fracture healing. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 1074–1081, 2009     

Inflammatory cells in normal human fracture healing

We studied inflammatory cells in specimens of callus taken from normally healing human fractures. Using immunohistochemistry, T-cells, B-cells, macrophages, HLA-DR expression and endothelial proliferation were assessed. Macrophages were present from an early stage but became less numerous later. T-cells were initially specifically recruited into the fracture site at the stage of granulation tissue, but subsequently excluded from areas of bone and cartilage formation. Inflammatory cells may control and coordinate fracture healing as has been proposed for soft tissue wound healing. The most likely mechanism for this is by the cytokines and growth factors which they are known to release.     

The effects of local insulin delivery on diabetic fracture healing

Several studies have documented that diabetes impairs bone healing clinically and experimentally. Systemic insulin treatment has been shown to ameliorate impaired diabetic bone healing. However, these studies failed to distinguish between a direct and a systemic effect of insulin upon bone healing. A novel intramedullary insulin delivery system was used in the diabetic BB Wistar femur fracture model to investigate the potential direct effects of insulin on bone healing. Insulin delivery at the fracture site normalized the early (cellular proliferation and chondrogenesis) and late (mineralized tissue, cartilage content and mechanical strength) parameters of diabetic fracture healing without affecting the systemic parameters of blood glucose. These results suggest a critical role for insulin in directly mediating fracture healing and that decreased systemic insulin levels in the diabetic state lead to reduced localized insulin levels at fracture site with concomitant increases in diabetic fracture healing time.     

煅狗骨对实验性骨折愈合作用的垂体TSH,GH细胞免疫细胞化学研究

为检测煅狗骨促进骨折愈合过程中垂体前叶促甲状腺激素(TSH)细胞和生长激素(GH)细胞结构和功能变化,本实验选用家兔54只,制成双侧桡骨标准骨折模型,分成煅狗骨用药组和对照组,术后每周定期取材。脑垂体常规石蜡包埋切片,行免疫细胞化学染色。结果显示对照组骨折后垂体TSH细胞及GH细胞数量均减少,而煅狗骨用药组则并未出现对照组的抑制性变化,TSH细胞数量一直维持较高水平,尤其GH细胞数量随术后时间延长而大幅度上升,因而说明煅狗骨能促进垂体TSH、GH细胞的功能,有利于骨折的愈合。     

Overview of the fracture healing cascade

Fracture healing is a dynamic process being governed by a variety of cellular elements and stimulating agents. Our knowledge in understanding the molecular and cellular processes occurring in healing fractures has vastly expanded as a result of the advances made in all aspects of medicine. The ability to manipulate mesenchymal stem cells and to deliver locally growth factors in order to create new bone has led to a proliferation of research papers. The purpose of this article is to provide a brief overview of the current level of understanding of the physiological processes regulating the healing of fractures.     

针灸治疗绝经后骨质疏松症的实验研究进展

以在体实验与离体实验作为文献的基本分类标准,进一步以各项实验室检测指标作为细化分类,分别对自2004年至2014年近11年来针灸治疗绝经后骨质疏松症作用的实验研究进行了由浅入深的分类综述。在体实验方面,分别从骨密度、骨组织形态学及骨生物力学、骨代谢生化指标、血清雌激素及细胞因子等方面进行了阐述,每个指标所属文献按时间先后顺序列出,每条文献详细介绍了动物分组、针灸选穴及治疗方法、检测指标及结果等;离体实验方面,整理总结了关于针刺血清对大鼠破骨细胞数量、骨吸收功能及其凋亡影响的实验研究进展。在此基础上作出评价,指出目前研究尚存在的问题,主要包括大鼠模型的差异、针灸取穴施术的多变,以及针灸治疗绝经后骨质疏松症作用机理未明等;提出了下一步探究的思路,以期为相关研究者提供借鉴与参考。     

针灸治疗膝骨性关节炎作用机制研究概况

膝骨性关节炎（knee osteoarthritis,KOA）是在正常关节软骨退变的基础上,经局部负荷不均、不良的生物力学结构改变加重关节软骨磨损,继而出现关节软骨变形、骨质增生及坏死,继发的炎症刺激,免疫学因素又导致关节功能障碍加重的慢性关节疾病。针灸治疗KOA疗效确切,但其治疗机制尚不明确。现总结相关文献研究,发现主要作用机制与抑制软骨细胞凋亡、调节分子生物学反应、调整生物力学、改善局部微循环、抗炎镇痛有关,旨在为临床诊疗提供思路,为进一步发展和推广针灸治疗KOA。